Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion

Liú, Dan; Hornsby, Peter J.

doi:10.1158/0008-5472.can-06-3452

Cited by 409 publications

(353 citation statements)

References 53 publications

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“…Further, and consistent with a SASP-induced EMT, CM from senescent, but not non-senescent, cells stimulated pre-malignant and malignant cancer cells to invade a basement membrane [21]. The secretion of MMP-2 and MMP-3 by senescent cells could also promote the invasion of multiple epithelial cell types [30,34,38,47,48]. Other proteases, such as uPA and its regulator (PAI1), are likewise implicated in cancer cell invasion.…”

Section: Effects Of the Sasp On Cell Migration And Invasionmentioning

confidence: 85%

“…Senescent, but not non-senescent, human and mouse fibroblasts can promote the progression of pre-malignant or malignant epithelial cells in mouse xenografts [21,[33][34][35]. In the following sections, we describe behavioral changes cells can undergo when residing in the proximity of senescent cells (see Fig.…”

Section: Emt Triggered By the Microenvironmentmentioning

confidence: 99%

“…Human SASPs can disrupt epithelial organization and promote the growth of pre-malignant epithelial cells in culture [21,30,33,34,36]. To determine whether mouse SASPs have similar biological activities, we compared the effects of mouse and human fibroblasts on the growth of premalignant or malignant mammary epithelial cells [21,35].…”

Section: Effects Of the Sasp On Epithelial Cell Proliferation And Difmentioning

confidence: 99%

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Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Laberge

Awad

Campisi

et al. 2011

Cancer Microenvironment

207

154

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Depending on the cell type and tissue environment, epithelial and mesenchymal cell phenotypes are not static and can be highly dynamic. Epithelial-mesenchymal transitions (EMTs) and reverse EMTs provide flexibility during embryogenesis. While EMTs are a critical normal process during development and wound healing, properties of the EMT have been implicated in human pathology, particularly cancer metastasis. A normal undamaged epithelium does not typically exhibit features of an EMT. However, particularly under the influence of the surrounding microenvironment, cancer cells may reactivate developmental phenotypes out of context in the adult. This reactivation, such as the EMT, can facilitate tumor cell invasion and metastasis, and therefore is a major mechanism of tumor progression. Conversely, cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, thereby constituting a potent tumor suppressive mechanism. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescenceassociated secretory phenotype (SASP) that turns senescent fibroblasts into pro-inflammatory cells having the ability to promote tumor progression, in part by inducing an EMT in nearby epithelial cells. Here, we summarize the potential impacts of SASP factors, particularly interleukins, on tissue microenvironments and their ability to stimulate tumor progression through induction of an EMT.

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Section: Effects Of the Sasp On Cell Migration And Invasionmentioning

confidence: 85%

Section: Emt Triggered By the Microenvironmentmentioning

confidence: 99%

Section: Effects Of the Sasp On Epithelial Cell Proliferation And Difmentioning

confidence: 99%

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Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Laberge

Awad

Campisi

et al. 2011

Cancer Microenvironment

207

154

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“…Fibroblasts in senescence develop a complex senescence-associated secretory phenotype in vitro and in vivo (42)(43)(44)(45). An increase in IL-6 production is one of the principal indicators of senescenceassociated secretory phenotype.…”

Section: Inhibitory Effect Of Endogenous P16 Ink4a On Il-6 Productionmentioning

confidence: 99%

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Murakami

Mizoguchi

Saito

et al. 2012

The Journal of Immunology

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Induction of cyclin-dependent kinase (CDK) inhibitor gene p16INK4a into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16INK4a also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16INK4a modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16INK4a suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16INK4a gene transfer accelerated LPS-triggered IL-1R–associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16INK4a-induced IL-6 suppression. Senescent macrophages with physiological expression of p16INK4a upregulated IL-6 production when p16INK4a was targeted by specific small interfering RNA. These findings indicate that p16INK4a promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16INK4a senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.

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“…18 Indeed, it has been demonstrated that proliferation of premalignant breast epithelial cells in vitro and tumor growth in vivo increased in the presence of senescent rather than early-passage fibroblasts. 19,20 Moreover, fibroblasts adjacent to the malignant tissue in ovarian cancer specimens, in contrast to those neighboring the normal epithelium, have been found to be senescent. 21 It has also been demonstrated that senescent fibroblasts promoted tumor-associated angiogenesis, 22 which could facilitate malignant progression.…”

mentioning

confidence: 99%

Senescent Peritoneal Mesothelial Cells Promote Ovarian Cancer Cell Adhesion

Książek

Mikuła-Pietrasik

Korybalska

et al. 2009

The American Journal of Pathology

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Adhesion of ovarian cancer cells to the peritoneal mesothelium is a key step in the malignant progression of the disease. In an in vitro study, we showed that the adherence of ovarian cancer cells (of the OVCAR-3, SKOV-3, and A2780 cell lines) to senescent human omentum-derived peritoneal mesothelial cells (HOMCs) was greater than to early passage cells. The process was mediated primarily by the increased interaction of the ␣5␤1 integrin on cancer cells with HOMC-associated fibronectin (FN). In comparison with early passage HOMCs, senescent cells exhibited increased FN mRNA expression levels and produced significantly more FN. To assess the effect of senescence-associated oxidative stress on FN release, HOMCs were rendered senescent by exposure to an oxidant, tert-butyl hydroperoxide. Treatment with tert-butyl hydroperoxide resulted in a significant increase in HOMC FN mRNA and protein expression levels. The effect of oxidative stress on FN synthesis was found to be mediated by transforming growth factor-␤1, whose signaling pathway was controlled at upstream and downstream levels by p38 MAPK. The activity of p38 MAPK increased markedly in senescent HOMCs. Treatment of HOMCs with antioxidants significantly attenuated senescence-associated increases in p38 MAPK activity, production of both transforming growth factor-␤1 and FN, and ovarian cancer cell adhesion. These data indicate that oxidative stress that accompanies senescence may increase Ovarian cancer is still associated with high mortality. The poor outcome is related to a large extent to metastatic spreading of cancer cells within the peritoneal cavity. Attachment of malignant cells to the peritoneal mesothelium is thought to be a critical step in peritoneal dissemination of the disease. Available data indicate that the process is mediated by interactions between extracellular matrix components produced by mesothelial cells and the corresponding adhesion molecules on ovarian cancer cells. A key role is thought to be played by CD44 and ␤1 integrin receptors and their ligands-hyaluronan, fibronectin (FN), and vitronectin. [2][3][4][5][6] FN is a ubiquitous constituent of extracellular matrix. Secreted by cells as a soluble dimer, it is then processed and assembled into insoluble fibrils at the cell surface. 7 FN is involved in many cellular functions including the maintenance of cell shape, tissue repair, cell differentiation, adhesion, and migration. These processes are primarily mediated by binding of the Arg-Gly-Asp (RGD) sequence of the FN molecule to integrin receptors (especially to ␣5␤1 and ␣ V ␤3).8 It has been demonstrated that FN released by peritoneal mesothelial cells stimulates ovarian cancer cell motility in vitro.9 Moreover, competitive inhibition of FN by RGD-containing peptides has been reported to decrease peritoneal spreading of ovarian cancer cells in mice. 10 More recently it has been demonstrated that the attachment of ovarian cancer cells to the peritoneum results in up-regulation of their matrix metalloproteinase-2, which cleaves mesot...

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Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion

Cited by 409 publications

References 53 publications

Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Senescent Peritoneal Mesothelial Cells Promote Ovarian Cancer Cell Adhesion

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